Atherosclerosis is a pathologic process with major clinical consequences. Macrophages are important mediators of atherosclerosis, but critical aspects of the cellular and molecular mechanisms by which macrophages affect atherosclerosis are unclear. Cell-surface receptors called integrins can direct many macrophage functions, and Dr. Alenghat has identified a new macrophage-specific signaling pathway that acts downstream of integrins and is required for normal macrophage migration, chemotaxis, and cytoskeletal remodeling. However, unlike many other macrophage signaling defects, the absence of a key protein in this pathway-Skap2-exacerbates atherosclerosis in a mouse model. Therefore, this integrin-mediated pathway appears to be atheroprotective. How can macrophages be responsible both for driving atherosclerosis and for limiting or modulating inflammatory processes? Dr. Alenghat's results point to an integrin-based level of processing that controls macrophage phenotype. Based on work to date, Skap2's signaling partners include one major inhibitory protein-Sirp?-that is controlled by integrin signals in macrophages. Understanding the mechanism by which such signaling controls a balance between inflammatory (activating) and anti- inflammatory (inhibitory) modes may point to rational new approaches for treatment of atherosclerosis. Here, Dr. Alenghat hypothesizes that integrin-mediated pathways dependent on Sirp?, Skap2, and other molecular partners direct a signaling switch in macrophages, and that these pathways modulate the inflammatory component of atherosclerosis, possibly by regulating intralesional macrophage dynamics. In three specific aims, Dr. Alenghat will: (1) characterize how the Skap2/Sirp? module directs signals through inhibitory and activating pathways to modulate macrophage cytoskeletal remodeling; (2) use mouse models to define the mechanism by which these integrin-mediated pathways control the inflammatory component of atherosclerosis; and (3) develop innovative techniques to study specialized in vitro and intralesional macrophage dynamics in order to understand how macrophages maintain lesional homeostasis. Successful completion of this project will provide new insights into the mechanisms underlying atherosclerosis and may aid in the identification of novel targets for therapeutic intervention to either treat or prevent this process. Dr. Alenghat is a physician-scientist who completed his medical and graduate education at Harvard Medical School and the Harvard Biophysics Program, respectively. He trained clinically in internal medicine and cardiovascular medicine at Brigham and Women's Hospital and is board certified in both fields. He is Instructor in Biological Chemistry and Molecular Pharmacology and Instructor in Medicine at Harvard Medical School, and he is a staff cardiologist at VA Boston Healthcare System. With a research background in vascular biology, integrin signaling, and mechanotransduction, Dr. Alenghat's long-term goal is to perform and direct cardiovascular basic and translational research as an academic cardiologist and a leader in his field. His immediate goal is to build on his current findings with new investigative directions, which would solidify his expertise in the field and facilitate his transition from mentored to independent investigator. Specifically, he wil acquire several new research skills, develop innovative techniques to assess atherosclerotic lesions, interact closely with both his mentor and an expert panel of advisors, present his work in the form of talks and publications in multiple venues, and acquire further training through the Harvard Catalyst Program that is specifically geared to facilitate the transition to independence. He will conduct his work with the laboratory of his mentor, Dr. David Golan, in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. This research environment has all the necessary facilities, equipment, expertise, and supportive training to complete the project successfully.